This project covers a broad base of studies aimed at assessing the epidemiology of the majority of hormonally-related cancers. Major efforts are underway for breast, endometrial, ovarian, prostate and testicular cancers. A variety of environmental, genetic and hormonal predictors of risk are under study. Two large efforts are underway to expand our knowledge regarding breast cancer. One study, which involves collaboration with extramural investigators, has involved collection of buccal swab specimens within the context of a large case-control study. This effort has required extensive methodologic work to determine the optimal means of collecting, processing and storing samples in order to maximize DNA yield. Another large case-control study in Poland has recently been expanded to include ovarian and endometrial cancers as well as breast cancer. This ambitious effort has been designed to assess the interactive effects of genetic and environmental determinants of risk. In addition, special components of the study are addressing in detail the effects of physical activity, occupational factors, and household chemical exposures. For physical activity, special efforts have been expended on improving exposure assessment, with women being asked to wear accelerometers to obtain more objective measures than interview data alone. The study also involves collection of tissue samples to enable precise tumor classification as well as assays of tumor biomarkers (including utilizing newly developed tissue microarray techniques). Breast cancer risk is also of major interest in a follow-up of a cohort of women previously screened for bone density. This resource, which previously involved collection of serologic samples and currently is collecting buccal swabs, will enable an assessment of the interrelationship of bone density, genetic factors and endogenous hormones in predicting subsequent cancer occurrence. In addition to breast cancer, several other hormonally-related cancer sites (e.g., endometrium, lung, colorectum) are of interest. A number of studies are ongoing to define etiologic factors for ovarian and endometrial cancers. A collaboration has recently been established with the Gynecologic Oncology Group to determine means of collecting epidemiologic data within the context of a number of ongoing trials. Such a venture should prove especially useful in assessing epidemiologic predictors and molecular markers associated with carefully defined histologic subgroups of tumors, as well as comparing the epidemiology of histologically similar but site diverse tumors. In addition, we are hopeful within either this setting or a prepaid health plan to initiate several studies to clarify the natural history of early ovarian and benign endometrial lesions. Efforts continue to identify risk factors for prostate cancer. In a multi-disciplinary case-control study that we undertook in a low risk population in China, we observed that body shape was strongly related to risk, an association that appeared to be partially mediated by serum insulin and insulin-like growth factor levels as well as vitamin D receptor gene polymorphisms. Physical activity, however, did not appear to be predictive of risk. Other genetic factors have also been of interest in this study. An examination of the CAG trinucleotide repeat in the polyglutamine regions of the androgen receptor gene confirmed that Chinese men have a longer repeat length than western men; in addition, a shorter repeat length appeared to confer a higher risk of clinically significant prostate cancer risk. Current efforts are assessing the etiologic role of other genetic and hormonal factors in this study. A pilot study has been undertaken to assess capabilities for measuring insulin-like gown factors in the Washington County Cohort Study. In addition, a methodologic study is ongoing in several different ethnic groups to measure endogenous hormones and genetic markers in prostate tissue and to compare these levels with those obtained using serologic samples. We have recently initiated a large case-control study of testicular cancer in collaboration with the U.S. Department of Defense. A unique resource of banked sera among the majority of recent military recruits will enable testing of a variety of pre-diagnostic biologic markers of interest for this tumor, including organochlorines as well as endogenous hormones. A number of other projects are ongoing to assess the etiologic role of endogenous hormones. In these studies, attention is focusing not only on classically accepted hormones, but also on some newly suggested predictors, including insulin-like and other growth factors. Further follow-up of participants in the Columbia, Missouri component of the Mayo Serum Bank is being pursued to expand upon previous findings and to enable additional hypotheses to be addressed. In a study using samples from the entire Mayo Serum Bank, serum hormone and growth factor levels are being compared among women with histologically classified non-neoplastic and malignant breast lesions. Relationships are also being assessed in several case-control studies, including studies of breast cancer among Asian-American and younger U.S. women and a study of prostate cancer in China. Although cervical cancer has not generally been recognized as a hormonally-related tumor, a number of risk factors, including parity and exogenous hormone use, support the need for further study of hormonal factors. Within the context of a large natural history study, we are attempting to assess the role of endogenous hormones to cervical abnormalities, particularly as they affect the progression and persistance of infection with the human papillomaviruses. Our research has also attempted to advance our understanding of predictors of endogenous hormones. This has included analyses within the control populations of several studies. Within two cohort studies (the Dietary Intervention Study of Children and the Portland Cervical Neoplasia Followup Study), efforts are underway to assess how hormone levels are influenced by a variety of genetic factors, including several hormone metabolizing genes. We are also in the process of establishing a laboratory to increase our understanding of endocrinologic markers that may be most worthy of pursuit in the many studies that are underway.